S162: SOMATIC GENETIC LANDSCAPE IN GATA2 DEFICIENCY PATIENTS
Authors: L. Largeaud, M. Collin, N. Monselet, F. Vergez, L. Larcher, P. Hirsch, N. Duployez, J. Bustamante, C. Bellanné-Chantelot, J. Donadieu, F. Sicre de Fontbrune, M. Nolla, C. Fieschi, F. Delhommeau, E. Delabesse, M. Pasquet
Journal: HemaSphere (2022)

Background: Heterozygous germline GATA2 mutations strongly predispose to myeloid malignancies, immunodeficiency, and/or lymphedema. The progression towards haematological diseases seems to be correlated with the acquisition of molecular and cytogenetic abnormalities. Aims: Our study therefore focuses on the biological characterization of the different progression stages of germline GATA2 deficiency patients and their correlation with clinic features. Methods: We describe here a cohort of 78 patients (62 from the French-Belgian cohort and 16 British patients). Molecular analysis by next generation sequencing (targeting 90 genes frequently mutated in myeloid malignancies with a sensitivity = 1%) was performed in 76 patients. Cytogenetic analyses were determined for 76 patients. Results: Median age of our cohort was 21.8 years [6months–62years]. 44 had missense mutations, 32 had null mutations, one intronic and one synonymous mutation. Our results showed a trend toward a younger age at diagnosis in patients harboring null mutations compared to patients with missense mutations (13 vs 17 years, p=0,086) and more chronic infections during follow-up (74% vs 25%, p<0,001). 55 karyotypic abnormalities were identified including monosomy 7 (29%), trisomy 8 (16%) and der (1;7) (9%). Moreover, 141 somatic mutations were identified targeting STAG2 (38%), ASXL1 (13%), SETBP1 (8%), EZH2 (4%) and RUNX1 (3%) genes. To better stratify patients, we defined 3 spectra based on morphological bone marrow analysis: 12 (15%) patients had spectrum 0 (normal bone marrow), 47 (60%) had spectrum 1 (hypoplastic marrow and/or low-grade myelodysplasia (MDS)) and 19 (25%) were classified as spectrum 2 (MDS with excess blasts, AML and CMML). We found a genotype-phenotype correlation: spectrum 1 is more associated with null mutations and spectra 0 and 2 with missense mutations (p=0.023). Patients in spectrum 0 exhibited no acquired molecular and karyotypic abnormalities. Spectrum 2 was enriched with mutations of SETBP1, RAS pathway genes, and RUNX1 as well as more other cytogenetic abnormalities excluding -7, tri8 and der(1;7) (p<0,001). The proportion of monosomy 7 was higher in spectrum 2 than in spectrum 1 without reaching the significance level (47% vs 28%). Conversely, STAG2 mutations were mainly found in spectrum 1. 53 STAG2 mutations were identified in 25 patients (1 to 8 mutations per patient), mostly at low mutated cell fraction (median: 6%). Follow-up of 3 patients with STAG2 clones in spectrum 1 showed no progression toward spectrum 2. Moreover, clonal hierarchy of 3 patients with STAG2 mutations in spectrum 2 showed that STAG2 mutations were subclonal events. Our results suggested that STAG2 mutation did not act as driver and could be related to clonal hematopoiesis. Interestingly, Stag2 KO mice showed an enrichment of GATA2 binding motif (Ochi et al. Cancer Discov 2020) which could lead to an increase of GATA2 activity. We speculate that in GATA2 deficiency syndrome, STAG2 mutations could induce a mechanism of indirect Somatic Genetic Rescue (SGR) by compensating the loss of GATA2 activity induced by the mutated allele. Image:Summary/Conclusion: This study reported that STAG2 mutations were recurrent in GATA2 deficiency clonal hematopoiesis. Some genetic abnormalities are associated with the leukemic transformation stage such as SETBP1, RAS pathway genes and other cytogenetic abnormalities. An improved ability to identify patients with high risk of developing leukemic transformation has the potential to improve clinical outcomes and help clinicians determine the optimal timing of bone marrow transplantation.